1. Field of the Invention
The present invention in general relates to natural stilbenoids. More specifically, the present invention relates to situin modulating stilbenoids, in specific orally bioavailable SIRT-1 enhancing compounds (i) 3,5-dimethoxy-3,4′-dihydroxystilbene and (ii) 2,3′,5′,6-tetrahydroxy-trans-stilbene, and compositions thereof. The present invention also discusses the novel enhanced anti-acne properties of 3,5-dimethoxy-3,4′-dihydroxystilbene and compositions thereof.
2. Description of Prior Art
SIRT1 is a member of the sirtuin family of NAD+-dependent deacetylases. SIRT1 is an enzyme which deacetylates proteins that contribute to cellular regulation (reaction to stressors, longevity). These enzymes have evolved to catalyze a unique reaction in which deacetylation of a lysine residue in a substrate protein is coupled to the consumption of NAD. The following prior art references discuss the biological nature and activity of SIRT1.
I. Frye, R. A. Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity. Biochem Biophys Res Commun 260, 273-9 (1999); II. Frye, R. A. Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. Biochem Biophys Res Commun 273, 793-8 (2000); III. Imai, S., Armstrong, C. M., Kaeberlein, M. & Guarente, L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 403, 795-800 (2000)].
The modulation of the activities of cellular protein substrates including PGC-1α, NCoR, p300, NFkB, FOXO, and p53 has been attributed to the biological effects of the enzyme on mitochondrial biogenesis, metabolism in muscle and adipose tissue, and cellular survival. Activation of SIRT1 protein results in improvement of insulin sensitivity, lower glucose levels; Thus SIRT1 inhibition has direct bearing on diabetic control, SIRT1 activation results in the increase in the number of mitochondria and improvement of their function. Increase in mitochondrial number has direct attributes to longevity of the cell. SIRT1 activation is related to decreased adipocity and tolerance to exercise. Thus SIRT1 activation has application in weight control and control of obesity. References include:                1. Bouras, T. et al. SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1. J Biol Chem 280, 10264-76 (2005);        2. Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011-5 (2004);        3. Luo, 3. et al. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 107, 137-48 (2001);        4. Motta, M. C. et al. Mammalian SIRT1 represses fork head transcription factors. Cell 116, 551-63 (2004);        5. Nemoto, S., Fergusson, M. M. & Finkel, T. SIRT1 functionally interacts with the metabolic regulator and transcriptional co-activator PGC-1 {alpha}. J Biol Chem 280, 16456-60 (2005);        6. Picard, F. et al. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 429, 771-6 (2004);        7. Rodgers, 3. T. et al. Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature 434, 113-8 (2005);        8. Van der Horst, A. et al. FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1). I Biol Chem 279, 28873-9 (2004);        9. Vaziri, H. et al. hSIR2 (SIRT1) functions as an NAD-dependent p53 deacetylase. Cell 107, 149-59 (2001);        10. Yeung, F. et al. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. Embo 3 23, 2369-80 (2004).        11. Elliot, P. J.; lirousek, J.; Sirtuins, Novel targets for metabolic diseases, Current Opinion in Investigational drugs, 9(4), 371-8 (2008)        
The ability of resveratrol to modulate sirtuin gene and protein expression has been well documented. Some important prior art in this regard include:                I. The protective action of resveratrol in upregulating the SIRT1-AMPK (AMP-activated kinase) signaling system in preventing alcohol induced fatty liver in ethanol-fed mice is documented in Am J Physiol Gastrointest Liver Physiol. 2008 October; 295(4):G833-42.        II. Pharmacological preconditioning by resveratrol in part is directed towards the compound's ability to activate SIRT1 in 1: Med Hypotheses. Aug. 9, 2008.        III. The ability of resveratrol to elevate glucose uptake in muscle cells through a mechanism involving sirtuins and AMP-kinase and possibly stimulation of GLUT4 transporter intrinsic activity has been implicated in Biochem Biophys Res Commun. Sep. 12, 2008; 374(1):117-22.        
Similarly, the ability of resveratrol to inhibit Propionibacterium acnes has been documented in 3 Antimicrob Chemother. 2007 June; 59(6):1182-4.
The principle objective of the present invention is to evaluate the bioavailability and sirtuin modulating ability of 3,5-dimethoxy-3,4′-dihydroxystilbene which are analogs of 3,5-dimethoxy-4′-hydroxystilbene (pterostilbene) which in turn are natural analogs of resveratrol. The invention also aims to evaluate the bioavailability and sirtuin modulating ability of 2,3′,5′,6-tetrahydroxy-trans-stilbene (gnetol).
It is also another objective of the present invention to evaluate 3,5-dimethoxy-3,4′-dihydroxystilbene (3-hydroxypterostilbene) for its potential to inhibit Propionibacterium acnes and cosmeceutical applications thereof.
The present invention fulfills the aforesaid objectives and provides further related advantages.